Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.

Background

An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease.

Method

Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231.

Results

In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC

Conclusions

These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies.

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Déclaration de conflit d'intérêts

Potential conflicts of interest. S. A., A. S. A., M. L. B., A. B., M. B., F. H., S. M., G. N., J. G. S., H. S., S. S. T., L. U., M. W., and T. Z. are employees of Pfizer and may hold stock or stock options. M. G. H.-M. is an advisor and has received research grants from Gilead Sciences, ViiV Healthcare, and Janssen. M. D. has received research funding from Novartis and Eli Lilly; consulting fees from Tillotts Pharma, ORIC Pharmaceuticals, Partner Therapeutics, SQZ Biotech, AzurRx, Eli Lilly, Mallinckrodt Pharmaceuticals, and Moderna; and honoraria from WebMD, Experts at Your Fingertips, Sandoz Academy, and UpToDate. M. D. is also a member of the Scientific Advisory Board for Neoleukin Therapeutics. P. L. was an employee of Pfizer at the time of the study and holds stock in Pfizer. All other authors report no potential conflicts.